ABSTRACT: Oral squamous cell carcinoma (oral SCC) accounts for most of the 500,000 worldwide incident cancers of the oral cavity and oropharynx. Although improvements in local control and survival have been achieved with the use of combined modality therapies, the overall 5 year survival rate for oral cancers have not improved significantly over the past 20 years. Local-regional relapse and distant metastasis after definitive therapy are a major cause of morbidity and mortality in oral SCC patients. This clinical problem has prompted us to identify genetic determinants that contribute to oral SCC relapse and metastasis. In preliminary studies, we demonstrate that: 1) PKCepsilon is significantly elevated in HNSCC, including oral and laryngeal SCC, 2) targeted inhibition of PKCepsilon, through siRNA , was sufficient to decrease cell invasion and motility in oral and laryngeal SCC, 3) Rho GTPases, specifically RhoA and RhoC, are downstream of the PKCepsilon signaling pathway and required for PKCepsilon-mediated cell invasion and motility, and 4) LIM domain kinase 2 and Stathmin, two proteins that are involved in cytoskeleton dynamics and cell motility, are identified as novel PKCepsilon substrates. Our preliminary observations build a strong case for the importance of PKCepsilon in establishing an aggressive, highly metastatic phenotype in oral SCC. We propose to extensive study the biological role of PKCepsilon in oral SCC, specifically we will focus on the molecular mechanism of PKCepsilon dysregulation, on the mechanism of PKCepsilon-mediated RhoA and RhoC activation, and to dissect the PKC?-mediated cell motility signaling network and determine the select PKC? nodes that are indispensable for cell motility in oral SCC. PROJECT NARRATIVE: This project is designed to extensively examine for the first time the role of PKCepsilon in the development of metastasis, an recalcitrant challenge in oral SCC. These experiments will provide significant advance in our knowledge of cancer cell signaling through PKCepsilon and will advance the development of a novel treatment strategies against metastatic oral squamous cell carcinoma.